Ureidopiperidino-ketoalkyl indoles

ABSTRACT

The invention provides compounds of general formula I ##STR1## and pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, wherein R represents hydrogen or lower alkyl, R 1  represents hydrogen or lower alkyl, R 2  represents hydrogen or lower alkyl, R 3  represents hydrogen, halogen, lower alkoxy, hydroxy, or lower alkyl, R 4  represents hydrogen, lower alkyl, cycloalkyl of 5 to 7 carbon atoms, thienyl, furyl, phenyl; phenyl mono- or disubstituted by halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl; or benzoyl, halobenzoyl, lower alkanoyl, cycloalkanoyl of 6 to 8 carbon atoms, or thienoyl, A represents an alkylene, mono- or diketo- or hydroxy-alkylene radical having from 1 to 5 carbon atoms and X is oxygen or sulphur. 
     The compounds exhibit action on the cardiovascular system particularly hypotensive and/or anti-hypertensive activity.

This application is a continuation-in-part of application, Ser. No.597,841, filed July 21, 1975, which is a continuation-in-part ofapplication, Ser. No. 511,415, filed Oct. 2, 1974, now abandoned.

The invention relates to novel indole derivatives to processes forpreparing them and to pharmaceutical compositions containing them.

The present invention provides compounds of the general formula:##STR2## and pharmaceutically acceptable acid addition and quaternaryammonium salts thereof, wherein R represents hydrogen or lower alkyl, R¹represents hydrogen or lower alkyl, R² represents hydrogen or loweralkyl, R³ represents hydrogen, halogen, lower alkoxy, hydroxy, or loweralkyl, R⁴ represents hydrogen, lower alkyl, cycloalkyl of 5 to 7 carbonatoms, thienyl, furyl, phenyl; phenyl mono- or disubstituted by halogen,lower alkyl, lower alkoxy, hydroxy, or trifluoromethyl; or benzoyl,halobenzoyl, lower alkanoyl, cycloalkanoyl of 6 to 8 carbon atoms orthienoyl, A represents an alkylene, mono- or diketo- or hydroxy-alkyleneradical having from 1 to 5 carbon atoms and X represents oxygen orsulphur.

The term "lower" in relation to alkyl and alkoxy radicals used hereinmeans that the radical contains from 1 to 6 carbon atoms. Usually suchradicals containing from 1 to 4 carbon atoms are preferred.

The alkylene radicals A may be straight chain or branched and when A isbranched it is preferably a straight chain alkylene containing up to 4carbon atoms in the chain and carrying one methyl substituent. A may befor example --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂--, ##STR3## --CO(CH₂)₃ -- or --CHOH(CH₂)₃ -- but is preferably CH₂--CH₂.

Examples of lower alkyl radicals for R, R¹, R², R³ or R⁴ are methyl,ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

R⁴ when heteroaryl can be thienyl e.g. 2-thienyl or furyl, e.g. 2-furyl.

Substituted phenyl radicals which can be used for R⁴ include phenylsubstituted by one or two substituents chosen from halogen such aschlorine, fluorine or bromine, lower alkoxy such as methoxy or ethoxy,lower alkyl such as methyl or ethyl, hydroxy, or trifluoromethyl.

Lower alkoxy radicals for R³ include methoxy, ethoxy, propoxy andbutoxy.

Cycloalkyl radicals for R⁴ are cyclopentyl cyclohexyl and cycloheptyl.

The radical R⁴ when acyl may be benzoyl, halobenzoyl, lower alkanoyl of2 to 7 carbon atoms e.g. acetyl or propionyl, or cycloalkanoyl of 6 to 8carbon atoms e.g. cyclohexanoyl, or thienoyl, e.g. 2-thienoyl.

Preferred compounds of formula I are those in which R¹, R² and R³ arehydrogen, those in which R⁴ is phenyl, 2-trifluoromethylphenyl, benzoyl,cyclohexanoyl or thienoyl, those in which R is hydrogen or methyl andthose in which A is --CH₂ CH₂ --

Specific preferred compounds of the invention are:

1-phenyl-3-[1-(2-[indolyl]ethyl)piperid-4-yl] urea;

1-[1-(2-[3-indolyl]ethyl) piperid-4-yl]-3-[2-trifluoromethylphenyl]urea;

1-benzoyl-3-[1-(2-[3-indolyl]ethyl) piperid-4-yl] urea;

1-phenyl-3[1-(2-[3-indolyl]ethyl) piperid-4-yl] thiourea,

1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-1-methyl-3-phenyl urea

1-cyclohexanoyl-3-[1-(2-[3-indolyl] ethyl)-piperid-4-yl] urea

1-(2-thienoyl)-3-[1-(2-[3-indolyl]-ethyl)-piperid-4-yl] urea

1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-1-methyl-3-phenyl thiourea

1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]thiourea

and their pharmaceutically acceptable acid addition salts.

The acid addition salts of the compounds of formula I which are withinthe scope of the invention include those formed from inorganic andorganic acids in particular pharmaceutically acceptable acid additionsalts such as the sulphate, hydrochloride, hydrobromide, hydro-iodide,nitrate, phosphate, sulphonate (such as the methane sulphonate andp-toluene sulphonate), acetate, maleate, fumarate, tartrate and formatesalts.

The quaternary ammonium salts include those formed with alkyl halides(e.g. methyl bromide or chloride) and aralkyl halides (e.g. benzylbromide or chloride).

The compounds of formula I exhibit pharmacological activity namelyaction on the cardiovascular system (particularly hypotensive and/oranti-hypertensive activity).

The compounds of formula I may be prepared in a number of ways bybuilding up the molecule from suitable starting materials in knownmanner. Such processes applied to the preparation of the novel compoundsof formula I are included in the scope of the invention.

The preferred method for preparing compounds of formula I comprisesreacting a compound of formula II ##STR4## (wherein R, R¹, R², R³ and Aare as defined in connection with formula I) with a compound of formulaIII

    r.sup.4 n═c═x                                      (iii)

wherein R⁴ is as defined in connection with formula I except hydrogenand X is oxygen or sulphur. When X is oxygen compound III is anisocyanate (R⁴ NCO,IIIa) and when X is sulphur compound III is anisothiocyanate (R⁴ NCS,IIIb).

If A contains a carbonyl group this reaction should be conducted undermild conditions to avoid the possibility of reaction between the amineII (when R is hydrogen) and the carbonyl group of another molecule ofamine II giving a Schiffs base. This does not apply when the carbonylgroup is adjacent to the piperidine nitrogen since it does not thenbehave as a ketone group. Usually the reaction to form the compound offormula I takes place at room temperature.

The starting materials of formula II wherein R is hydrogen may beprepared by methods described in our British Specification No.1,218,570. The starting materials of formula II wherein R is lower alkylmay be prepared by alkylating corresponding compounds of formula IIwherein R is hydrogen, or by methods analogous to those described inSpecification No. 1,218,570.

Compounds of formula I wherein R is hydrogen may be prepared byhydrolysis of the corresponding compounds of formula I where R⁴ is acyle.g. benzoyl or halobenzoyl.

A second method for preparing compounds of formula I comprises reactinga compound of formula (IV) ##STR5## wherein R¹, R², R³, and A are asdefined in connection with formula I, and Y is a halogen atom or anequivalent replaceable atom or radical for example an organic sulphonylradical such as a tosyl radical, with a compound of formula (V) ##STR6##wherein R, R⁴ and X are as defined in connection with formula I.

Compounds of formula IV may be prepared as described in BritishSpecification 1,218,570. Compounds of formula (V) may be prepared byknown methods.

A third method of preparing the compounds of formula I comprisesreacting a compound of formula ##STR7## (wherein R¹, R², R³, X and A areas defined in connection with formula I) with an amine of formula R⁴ NH₂(X) wherein R⁴ is as defined in connection with formula I excepthydrogen and acyl.

When A contains a carbonyl group care should be taken to avoid reactionbetween the amine (X) and the carbonyl group except when the carbonylgroup is adjacent to the piperidine nitrogen. Compounds of formula (VII)(wherein neither A nor R³ contain a hydroxy group and X is sulphur) maybe prepared by reacting an amine of formula II wherein R is hydrogeneither with (a) thiophosgene then calcium oxide or (b) carbon disulphidefollowed by ammonia to form a compound of formula IX ##STR8## which isthen treated with a heavy metal salt MB₂, wherein M is a divalent heavymetal and B₂ is two monovalent or one divalent anion. Examples of MB₂are CuSO₄, PbCO₃, FeSO₄ and Pb(NO₃)₂.

Compounds of formula VII wherein X is oxygen and neither A nor R³contain a hydroxy group may be prepared by treatment of a compound offormula II, wherein R is H with phosgene followed by treatment of theproduct with calcium oxide according to the following reaction scheme:##STR9##

If a compound of formula I is prepared in which the chain A contains oneor more carbonyl functions, then this chain may be selectively reducede.g. with an alkali-metal borohydride, except when the carbonyl group isadjacent to the piperidine nitrogen. Thus the COCH₂ residue may bereduced with sodium borohydride to give the --CH(OH)CH₂ -- residue. WhenX is oxygen a compound of formula I wherein A contains one or morecarbonyl functions may be reduced by a hydride transfer agent(particularly lithium aluminium hydride). Thus the oxalyl residue COCOmay be reduced under mild conditions to the --CH(OH)CH₂ -- residue orunder more drastic conditions to the --CH₂ CH₂ -- residue.

A further method for preparing compounds of formula I, comprisesreducing a corresponding compound of formula (VI) or (VIa) ##STR10##wherein R, R¹, R², R³, R⁴, and A are as defined in connection withformula I and X₁ ⁻ is an anion e.g. a halide ion.

A compound of formula (VIa) may be reduced with an alkali metalborohydride e.g. sodium borohydride to give a corresponding compound offormula (VI). Compounds of formula VIa or VI (wherein X is oxygen) mayalso be reduced by catalytic hydrogenation e.g. in the presence of Raneynickel or a platinum catalyst to a corresponding compound of formula I.

Another method of preparing compounds of formula I wherein X is oxygenand A is an alkylene radical comprises reacting a compound of formula(VIIa) ##STR11## wherein R¹, R² and R³ are as defined in connection withformula I and A is an alkylene radical, with a compound of formula (V)as defined above wherein X is oxygen.

The reaction is preferably carried out in the presence of a catalyst,for example Raney nickel. An organic solvent, which is inert under thereaction conditions, is usually used for example xylene, toluene orbenzene. Preferably the reaction is carried out by heating the reactantsunder reflux in a water-immiscible organic solvent, for example xylene,and removing the water formed during the reaction by azeotropicdistillation. If necessary, reactive substituent groups can be blockedduring a reaction and released later.

Compounds of formula (I) wherein X is oxygen may also be prepared bytreating a compound of formula (VIII) ##STR12## wherein R, R¹, R², R³,R⁴ and A are as defined in connection with formula I and R⁵ is an arylmethyl radical and X₁ ⁻ is an anion e.g. a halide ion, under mildconditions such as to remove the group R⁵. Preferably the group R⁵ isremoved by hydrogenolysis under standard conditions e.g. using anappropriate catalyst such as a palladium on carbon catalyst, a platinumcatalyst or a nickel catalyst. In this reaction a mono or diketo loweralkylene radical A may also be reduced to a corresponding hydroxy loweralkylene radical A. If the keto compound is desired it can be obtainedby oxidation of the final product.

Instead of a compound of formula (VIII) wherein R⁵ is as defined aboveany other starting material where R⁵ is an organic group which can bereadily removed under mild conditions can be used.

Other conditions which may be effective to remove the group R⁵ aretreatment with acid e.g. with acetic acid or hydrochloric acid to removea trityl group or treatment with alkali metal in liquid ammonia.

Examples of groups R⁵ in the starting materials of formula (VIII) arearylmethyl radicals such as benzyl, diphenylmethyl, trityl ornaphthlmethyl, benzyl being preferred.

A method for preparing compounds of formula (I) wherein R⁴ is hydrogenand X is oxygen comprises reacting a compound of formula (II) withnitrourea (H₂ NCONH.NO₂).

Once a compound of general formula (I) has been prepared, then ifnecessary one or more substituents in the molecule may be converted toanother substituent within its own meanings specified in connection withformula (I).

When a compound of formula (I) is produced wherein the R³ representslower alkoxy or aryl-lower alkoxy hydrolysis or dealkylation to thecorresponding hydroxyl compound may be brought about in known manner.

A further method for preparing compounds of formula (I) wherein R⁴ is anacyl radical namely benzoyl, halobenzoyl, lower alkanoyl, cycloalkanoylof 6 to 8 carbon atoms or thienoyl comprises reacting a compound offormula I wherein R⁴ is hydrogen with the appropriate acylating agentsuch as an acid chloride or bromide.

If necessary, in any of the reactions hereinbefore described, reactivesubstituent groups may be blocked during a reaction and released at alater stage.

The invention also includes pharmaceutical compositions containing asactive ingredient an active compound of formula I as above defined. Theactive compound may be micronised if desired. In addition to the activeingredient, the compositions also contain a non-toxic carrier. Anysuitable carrier known in the art can be used to prepare thepharmaceutical compositions. In such a composition, the carrier may be asolid, liquid or mixture of a solid and a liquid. Solid formcompositions include powders, tablets and capsules. A solid carrier canbe one or more substances which may also act as flavouring agents,lubricants, solubilisers, suspending agents, binders, ortablet-disintegrating agents; it can also be an encapsulating material.In powders the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 to 99,preferably 10-80% of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methyl cellulose, sodiumcarboxymethyl cellulose, a low melting wax, and cocoa butter. The term"composition" is intended to include the formation of an activeingredient with encapsulating material as carrier to give a capsule inwhich the active ingredient (with or without other carriers) issurrounded by carrier, which is thus in association with it. Similarlycachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable sterile liquid carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufficiently soluble it can be dissolvedin normal saline as a carrier; if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene glycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable. In other instances compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxy-methyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilised by intramuscular,intraperitoneal or subcutaneous injection. In many instances, a compoundis orally active and can be administered orally either in liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form. Insuch form, the composition is sub-divided in unit doses containingappropriate quantities of the active ingredients; the unit dosage formcan be a packaged composition, the package containing specificquantities of compositions, for example packeted powders or vials orampoules. The unit dosage form can be a capsule, cachet or tabletitself, or it can be the appropriate number of any of these in packageform. The quantity of active ingredient in a unit dose of compositionmay be varied or adjusted from 5 mg or less to 500 or more, according tothe particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence of carrier wherethe compounds are in unit dosage form.

The following examples illustrate the invention. Temperatures are in °C.

EXAMPLE 1 1-Phenyl-3-[1-(2-[3-indolyl]ethyl piperid-4-yl]urea

To a solution of 3-[2-(4-aminopiperidyl)ethyl]indole hydrate (1.31 g.)in warm dry benzene (125 ml.), was added phenyl isocyanate (0.63 g. 5%excess) in benzene (25 ml.).

The mixture was stirred at room temperature overnight and the titlecompound (1.74 g.) was filtered off. This was converted to thehydrochloride (1.39 g.) m.p. 214°-219° in ethanol-HCl/ether.

C₂₂ H₂₆ N₄ O HCl 1/2H₂ O requires C, 64.77; H, 6.92; N, 13.74. Found: C,64.69; H, 6.91; N, 13.45%

The product exhibited very good hypotensive activity and alsoanti-hypertensive activity.

EXAMPLE 2 1-(4-Chlorophenyl)-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea

Condensation of 3-[2-(4-aminopiperidyl)ethyl]indole, hydrate (1.05 g.)and 4-chlorophenyl isocyanate (0.65 g., 5% excess) in the manner ofExample (1), gave the crude title compound (1.55 g.) from which a purehydrochloride hemi-hydrate (1.41 g, m.p. 244.4° (dec.)) was obtained bytreatment with ethanolic HCl/ether.

C₂₂ H₂₅ CLN₄ O.HCl. 1/2H₂ O requires: C, 59.72; H, 6.15, N, 12.66.Found: C, 60.02; H, 6.33; 12.36%

The product exhibited antihypertensive activity.

EXAMPLE 3 1-[3,4-Dichlorophenyl]-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea.

Condensation of 3-[2-(4-aminopiperidyl)ethyl]indole, hydrate (1.31 g.)and 3,4-dichlorophenyl isocyanate (0.99 g., 5% excess) in the manner ofExample 1 gave the crude title compound (2.03 g.) from which a purehydrochloride (1.70 g., m.p. 258.4°, dec.) was obtained by treatmentwith ethanolic HCl/ether.

C₂₂ H₂₄ Cl₂ N₄ O HCl requires: C, 56.48; H, 5.39; N, 11.98. Found: C,56.69; H, 5.53; N, 11.84%.

The product exhibited hypotensive activity.

EXAMPLE 4 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-[4-methoxyphenyl]urea

Condensation of 3-[2-(4-Aminopiperidyl)ethyl]indole, hydrate (1.31 g.)and 4-methoxyphenyl isocyanate (0.78 g., 5% excess) in the manner ofExample 1 gave the crude title product (1.86 g.) from which a purehydrochloride, hydrate (1.96 g., 220.4°, dec.) was obtained by treatmentwith ethanolic HCl/ether.

C₂₃ H₂₈ N₄ O₂. HCl. H₂ O requires C, 61.81; H, 6.99; N, 12.53. Found: C,62.22; H, 6.84; N, 12.40%

The product exhibited hypotensive and antihypertensive activity.

EXAMPLE 5 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-[3-tolyl]urea

Condensation of 3-[2-(4-Aminopiperidyl)ethyl]indole, hydrate (1.31 g.)and 3-tolyl isocyanate (0.70 g., 5% excess) in the manner of Example 1gave the crude title compound (1.70 g.) from which was obtained a purehydrochloride (1.57 g., m.p. 228.9°, dec.) by treatment with ethanolicHCl/ether.

C₂₃ H₂₈ N₄ O HCl requires: C, 66.93; H, 7.08; N, 13.57. Found: C, 67.01;H, 7.21; N, 13.66%

The product exhibited hypotensive activity.

EXAMPLE 61-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-[2,6-dimethylphenyl]urea

Using the procedure of Example 14-amino-1-[2-(3-indolyl)ethyl]piperidine, hydrate (1.307 g) and2,6-dimethylphenyl isocyanate (0.688 g., 25% excess) gave the titlecompound as the hydrochloride (1.110 g, 52%) m.p. 329.7° (dec).

C₂₄ H₃₀ N₄ O.HCl requires: C, 67.53; H, 7.32; N, 13.12. Found: C, 67.55;H, 7.50; N, 12.63%

The product exhibited hypotensive activity in a standard test procedure.

EXAMPLE 71-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-[2-trifluoromethylphenyl]urea

Using the procedure of Example 14-amino-1-[2-(3-indolyl)ethyl]piperidine, hydrate (1.307 g.) and2-trifluoromethylphenyl isocyanate (0.982 g., 5% excess) gave the titlecompound as the hydrochloride (1.835 g., 82%) m.p. 233.6° (dec)

C₂₃ H₂₅ N₄ O.HCl requires: C, 59.18; H, 5.61; N, 12.00. Found: C, 59.28;H, 5.79; N, 11.66%

The product exhibited marked hypotensive activity in a standard testprocedure.

EXAMPLE 8 1-Benzoyl3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea

Using the procedure of Example 14-amino-1-[2-(3-indolyl)-ethyl]piperidine, hydrate (1.307 g.) andbenzoyl isocyanate (1.471 g.) gave the title compound as thehydrochloride (1.436 g., 63%), m.p. 248.0° (dec).

C₂₃ H₂₆ N₄ O₂ HCl requires: C, 64.73; H, 6.38; N, 13.12. Found: C,64.43; H, 6.66; N, 13.11.

The product is an intermediate for the next Example and also exhibitedmarked hypotensive activity and good antihypertensive activity.

EXAMPLE 9 1-[1-(2-[3-Indolyl] ethyl)piperid-4-yl]urea

1-benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea hydrochloride(1.180 g.) was refluxed in 2N sodium hydroxide solution (20 ml) for 1hour. The reaction mixture was cooled and the title compound wasfiltered off, (0.678 g., 86%) m.p. 212.2° (dec).

C₁₆ H₂₂ N₄ O requires: C, 67.10; H, 7.74; N, 19.57. Found C, 67.56; H,7.74; N, 19.35%.

The product exhibited hypotensive effects, but of short duration, at lowdoses in a standard test procedure. It also exhibited anti-hypertensiveactivity.

EXAMPLE 10 1-Phenyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl] thiourea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate (1.31 g, 0.005 mole)was dissolved in benzene (125 ml) and phenyl isothiocyanate (0.74g,0.0055 mole) added dropwise with stirring. After 24 hr., the mixture wasfiltered to give the title compound (free base) as a white amorphoussolid (1.76g). This was dissolved in a minimum of hot ethanol, saturatedethanol-HCl added until acid, and then the solution allowed tocrystallise. Filtration afforded the title compound hydrochloride ascolourless prisms (1.75g), m.p. 224.8°.

Analysis Found: C, 63.67; H, 6.74; N, 13.32 C₂₂ H₂₆ N₄ S.HCl requires C,63.67; H, 6.56; N, 13.50%

The product exhibited hypotensive and anti-hypertensive activities.

EXAMPLE 111-(4-Chlorophenyl)-3[1-(2-[3-indolyl]ethyl)piperid-4-yl]thiourea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with4-chlorophenyl isothiocyanate in the manner described in Example 10 toobtain the title compound as the hydrochloride.

EXAMPLE 121-[3,4-Dichlorophenyl]-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with3,4-dichlorophenyl isothiocyanate in the manner described in Example 10to obtain the title compound as the hydrochloride.

EXAMPLE 131-[4-Methoxyphenyl]-3[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea

4-Amino-1-[2-(3-indolyl)ethyl] piperidine hydrate is treated with4-methoxyphenyl isothiocyanate in the manner of Example 10 to obtain thetitle compound as the hydrochloride.

EXAMPLE 14 1-[3-Tolyl]-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with 3-tolylisothiocyanate in the manner of Example 10 to obtain the title compoundas the hydrochloride.

EXAMPLE 151-[2-Trifluoromethylphenyl]-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with2-trifluoromethylphenyl isothiocyanate in the manner of Example 10 togive the title compound at the hydrochloride.

EXAMPLE 16 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-cyclohexyl urea

4-Amino-1-[2-(3-indolyl)ethyl]piperidine, hydrate (1.307 g, 0.005 mole)in benzene (50 ml.) was treated with cyclohexyl isocyanate (0.688 g,0.0055 mole) and the mixture stirred for 18 hrs. Filtration afforded thetitle compound as colourless prisms (1.893 g), m.p. 203.8°.

Analysis: Found: C, 71.74; H, 9.05; N, 14.91 C₂₂ H₃₂ N₄ O requires C,71.70; H, 8.75; N. 15.21%

The product exhibited hypotensive activity.

EXAMPLE 171-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-3-(3-trifluoromethylphenyl)urea

3-[2-(4-Aminopiperidyl)ethyl]indole hydrate (1.31g, 0.005 mole) wasreacted with m-trifluoromethylphenyl isocyanate (1.03g, 0.0055 mole) inthe manner of Example 16 to give the title compound hydrochloride(0.87g), m.p. 200.0°.

Found: C, 59.51; H, 5.84; N, 11.95 C₂₃ H₂₅ F₃ N₄ O.HCl requires C,59.11; H, 5.57; N, 11.99%

The product exhibited hypotensive activity.

EXAMPLE 18 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-1-methyl-3-phenyl urea

3-[2-(4-Methylaminopiperidyl)ethyl]indole (1.28 g, 0.005 mole) andphenyl isocyanate (0.66g, 0.0055 mole) were condensed in the manner ofExample 16 to give the title compound hydrochloride (0.69g), m.p.217.6°. Found: C, 65.85; H, 7.37; N, 13.03 C₂₃ H₂₈ N₄ O. HCl. 1/4 H₂ Orequires C, 66.17; H, 7.24; N, 13.42%

The product exhibited marked hypotensive activity.

EXAMPLE 19 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]-1-methyl-3-phenylthiourea

3-[2-(4-Methylaminopiperidyl)ethyl]indole (1.28g, 0.005 mole) wasstirred in dry benzene (75 ml) and treated with phenyl isothiocyanate(0.74g, 0.0055 mole). Stirring was continued for 24 hr. and the mixtureevaporated to give the title compound, which was converted to thehydrochloride by addition of hydrogen chloride in ethanol andprecipitation with ether. Yield, 0.95g, m.p. 193.7°.

Analysis: Found: C, 64.05; H, 6.99; N, 13.11 C₂₃ H₂₈ N₄ S.HCl requiresC, 64.39; H, 6.81; N, 13.06%.

The product exhibited good hypotensive activity.

EXAMPLE 20 1-Benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]thiourea

To a stirred solution of ammonium thiocyanate (2.28g) in dry acetone (20ml) was added a solution of benzoyl chloride (4.22g) in dry acetone (20ml). This mixture was stirred at 45° for 5 min. then treated with asolution of 3-[2-(4-aminopiperidyl)-ethyl]indole (7.84g) in dry acetone(30 ml). After refluxing for 25 min, the mixture was cooled, poured intowater (250 ml) and the liberated oil extracted into chloroform.Evaporation of the dried (MgSO₄) extract afforded the title compoundwhich was crystallised from EtOH-HCl/Et₂ O as the hydrochloride (1.65g), m.p. 212°-215°.

Found: C, 61.70; H, 6.43; N, 12.14. C₂₃ H₂₆ N₄ OS. HCl. 1/4 H₂ Orequires C, 61.74; H, 6.19; N, 12.52%.

The product exhibited hypotensive activity.

EXAMPLE 21 1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]thiourea

1-Benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea (2.21g) wasrefluxed in water (20 ml) containing sodium hydroxide (1.0 g) for 5 min.The mixture was cooled and filtered to afford the title compound(1.59g). Crystallisation from EtOH-HCl/ether afforded the hydrochloride(1.467g), m.p. 228°-9°.

Found: C, 56.78; H, 7.20; N, 16.42 C₁₆ H₂₂ N₄ S. HCl requires C, 56.70;H, 6.84; N. 16.53%.

The product exhibited hypotensive activity.

EXAMPLE 22 1-Methyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea

Following the procedure of Example 1 3-[2-(4-aminopiperidyl)ethyl]indoleis reacted with methyl isocyanate to give the title compound which isconverted to the hydrochloride.

EXAMPLE 23 1-(2-Thienyl)-3-[1-(2-[3-indolyl]ethyl)piperidyl]thiourea

Following the procedure of Example 103-[2-(4-aminopiperidyl)ethyl]indole is treated with 2-thienylisothiocyanate to give the title compound which is converted to thehydrochloride.

EXAMPLE 24 1-(2-Furyl)-3-[1-[3-indolyl]ethyl)piperidyl]urea

Following the procedure of Example 1 3-[1-(4-aminopiperidyl)ethyl]indoleis treated with 2-furyl isocyanate to give the title compound which isconverted to the hydrochloride.

EXAMPLE 25 1-Acetyl-3-[1-(2-[3-indolyl]ethyl)piperidyl]urea

3-[2-(4-Aminopiperidyl)ethyl]indole is treated with acetyl isocyanatefollowing the procedure of Example 1 to give the title compound which isconverted to the hydrochloride.

EXAMPLE 26 1-Cyclohexanoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea

To a suspension of 1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea (0.35 g)in dry benzene (2 ml) was added anhydrous pyridine (0.12 g) and thencyclohexanoyl chloride (0.18 g). After refluxing the mixture for 2 forhours, the title compound was filtered off, washed, dried and convertedin ethanolic hydrogen chloride to the hydrochloride (0.52 g) m.p. 236.3°C.

Analysis Found: C, 60.55; H, 7.59; N, 12.14%. C₂₃ H₃₂ N₄ O₂.HCl requiresC, 60.64; H, 7.85; N, 12.30%.

The product exhibited very good hypotensive activity.

EXAMPLE 27 1-(2-Thienoyl)-3-[1-(2-[3-indolyl]-ethyl)-piperid-4-yl]urea

1-[1-(2-[3-Indolyl]ethyl)piperid-4-yl]ura (0.35 g) was treated with2-thienoyl chloride (0.18 g) in the manner of Example 26 to give thetitle compound as the hydrochloride (0.13 g) m.p. 247.3° C.

Analysis Found: C, 56.76; H, 5.71; N, 12.67. C₂₁ H₂₄ N₄ O₂ S.HClrequires C, 57.06; H, 5.93; N, 12.68%.

The product exhibited marked hypotensive activity.

EXAMPLE 28 1-Benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea A.4-Amino-1-[4-(3indolyl )-4-oxobutyl]piperidine

A solution of 4-benzamido-1-[4-(3-indolyl)-4-oxobutyl] piperidinehydrochloride (8.5g, 0.02 mol.) and potassium hydroxide (32g) in ethanol(80 ml.) was heated under reflux for 24 hours. The solution was thencooled, diluted with water and extracted 3 times with chloroform (100ml.). The extract was dried and evaporated, the residue was dissolved inwarm ethanol (20 ml.) and acidified with ethanolic hydrogen chloride.

After cooling in ice the precipitated solid was collected, washed oncewith ethanolic hydrogen chloride, and once with ethyl acetate to give4-amino-1-[4-(3-indolyl)-4-oxobutyl]piperidine dihydrochloride (6.6g,90.5%) hemihydrate m.p. 299-31° C.

Analysis Found C, 55.88; H, 7.06; N, 11.35%. C₁₇ H₂₃ N₃ O. 2HCl 1/2H₂ Orequires C, 55.59; H, 7.13; N, 11.43%,

B. 1-Benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea

An ice cooled solution of the free base of the above 4-amino compound(2.1g, 0.075 mol) in hexamethylphosphoramide (10 ml) was treated withbenzoylisocyanate (1.35 g, 30% excess). The solution was stirred for 30minutes then diluted with water. A gum precipitated and was trituratedwith chloroform to give a solid product which was collected byfiltration (1g, 48%). The hydrochloride was prepared by precipitationfrom ethanolic hydrogen chloride solution by addition of ethyl acetate.This product 1-benzoyl-3 [1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]ureahydrochloride hemihydrate melted at 180° C, resolidified and remelted at238°-240° C. Analysis: Found C, 62.64; H, 6.10; N, 11.54. C₂₅ H₂₈ N₄ O₃: HCl: 1/2H₂ O requires C, 62.82; H, 6.33; N, 11.72%.

The product exhibited hypotensive activity.

The product may be prepared by the alternative method of treating1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea with benzoyl chloridefollowing the procedure of Example 1.

EXAMPLE 29 1-(2-Thienoyl)-3-[1-(4-[3-indolyl]oxobutyl)piperid-4-yl]urea

A. 1-Benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea free base(2.9g), sodium hydroxide (0.54g), ethanol (15ml) and water (5ml) wererefuxed for two hours and then poured into cold water, the precipitatedsolid was filtered off and crystallised from ethanol to give1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea.

B. The urea obtained in part A above was treated with 2-thienoylchloride following the procedure of Example 27 to give the titlecompound which was converted to the hydrochloride mp 246°-7° C.

EXAMPLE 30 1-[1(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]-3-phenylurea

A solution of 4-amino-1-[4-(3-indolyl)-4-oxobutyl] piperidine (1.70g,0.0060 mole) and phenyl isocyanate (0.74g, 0.0062 mole) in dry benzene(40 ml) was stirred for 24 hours, protected by a silica-gel guard tube.The solution was evaporated to yield an oil, which was recrystallisedtwice from ethanol. The crystals were then dissolved in the minimumvolume of methanol, and the solution acidified (pH2) with ethanolichydrogen chloride. Dilution with ether precipitated pale pink crystals,which were removed by filtration, washed with a little ether and driedto yield 1-[1-(4-(3-indolyl)-4-oxobutyl)piperid-4-yl]-3-phenylurea asthe hydrochloride (1.02g, 39%) m.p. 243°-4° C. Analysis: Found: C,65.19; H, 6.67; N, 12.37. C₂₄ H₂₈ N₄ O₂. HCl requires C, 65.36; H, 6.63;N, 12.71%.

We claim:
 1. A compound of formula I ##STR13## and pharmaceuticallyacceptable acid addition and quaternary ammonium salts thereof, whereinR represents hydrogen or lower alkyl, R¹ represents hydrogen or loweralkyl, R² represents hydrogen or lower alkyl, R³ represents hydrogen,halogen, lower alkoxy, hydroxy, or lower alkyl, R⁴ represents hydrogen,lower alkyl, cycloalkyl of 5 to 7 carbon atoms, thienyl, furyl, phenyl;phenyl mono- or disubstituted by halogen, lower alkyl, lower alkoxy,hydroxy, or trifluoromethyl; or benzoyl, halobenzoyl, lower alkanoyl,cycloalkanoyl of 6 to 8 carbon atoms, or thienoyl, A represents amonoketoalkylene radical having from 1 to 5 carbon atoms and X is oxygenor sulphur.
 2. A compound as claimed in claim 1, which is1-benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea or apharmaceutically acceptable acid addition salt thereof.
 3. A compound asclaimed in claim 1, which is1-(2-thienoyl)-3-[1-(4-[3-indolyl]oxobutyl-piperid-4-yl]urea or apharmaceutically acceptable acid addition salt thereof.
 4. A compound asclaimed in claim 1, which is1-[1(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]-3-phenylurea or apharmaceutically acceptable acid addition salt thereof.